Monoclonal antibody-mediated depletion of CD4+ Th and CD8+ Tc subsets in street rabies virus resistant strains of mice was used to determine the role of each subset in host immunity. Depletion of CD4+ Th was associated with a complete loss of resistance in both SJL/J an BALB/cByJ mice, while depletion of CD8+ Tc was without effect in either strain. Animals lacking CD4+ T cells as a result of treatment also failed to mount an IgG neutralizing response to rabies viral antigens, although IgM responses were intact. This data support previous findings on the protective role of IgG but not IgM neutralization responses in rabies disease. The data also argue against a role for cytotoxic T cells in the prevention or elimination of rabies virus infection in the central nervous system, since intact or CD8 depleted BALB/cByJ mice retain the capacity to clear a transient viral infection of the CNS. These findings were published in the Journal of Virology. Studies were also initiated on the role of macrophages in host resistance to street rabies virus. Susceptible strains of mice such as A/WySn or A.SW express a number of defects in macrophage responsiveness to IFN that have been related to host susceptibility to bacterial disease. A strain mice are also deficient in production of C5, and thus in release of the C5a macrophage chemotactic factor. Experiments to compare the peritoneal inflammatory responses of susceptible A.SW and resistant SJL/J mice revealed that A.SW mice are unable to mount a rapid and effective macrophage inflammatory response after intraperitoneal infection with street rabies virus. These animals can be protected, however, by pretreatment with an adjuvant containing trehalose dimycolate developed by Ribi Laboratories. Adjuvant pretreatment results in a 5 to 7 fold increase in the number of inflammatory cells present in the peritoneum at the time of infection. Experiments are currently underway to define any qualitative differences that may exist in macrophage activity of susceptible and resistant hosts. Results will be submitted for publication.